Sitagliptin, (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-dien-4-yl]-4-(2,4,5-trifluorophenyl)butan-↑-one, has the following chemical structure:

Sitagliptin is an orally-active dipeptidyl peptidase-4 (DPP-IV) enzyme inhibitor that improves glycemic control in patients with Type 2 diabetes mellitus by slowing the inactivation of incretin hormones. Sitagliptin may be used as a monotherapy, as an adjunct to diet and exercise, or in combination with metformin or a PPARγ agonist (e.g., thiazolidinediones). Sitagliptin is currently marketed in its phosphate salt in the United States under the tradename JANUVIA™ in its monohydrate form JANUVIA™ is indicated to improve glycemic control in patients with type 2 diabetes mellitus.
U.S. Pat. No. 6,699,871 (“the '871 patent”) discloses a class of beta-amino-tetrahydrotriazolo[4,3-a]pyrazines such as Sitagliptin and its hydrochloride salt form, a potent inhibitor of DPP-IV enzyme. Other pharmaceutically acceptable salts of this compound are generically encompassed within the scope of the '871 patent. It also discloses a process for the preparation of sitagliptin and related compounds.
U.S. Pat. No. 7,326,708 discloses dihydrogen phosphate salt of sitagliptin and crystalline hydrate thereof, in particular a crystalline monohydrate and processes for the preparation thereof. Crystalline polymorphs of sitagliptin dihydrogen phosphate anhydrate such as Form I, Form II, Form III and Form IV are disclosed in Patent publication No. WO 2005/020920 and WO 2005/030127. Amorphous sitagliptin dihydrogen phosphate is disclosed in Patent publication No. WO 2006/033848.
Patent publication No. WO 2005/072530 discloses crystalline acid addition salts of sitagliptin and hydrates thereof, wherein the acid addition salt is selected from the group consisting of hydrochloric acid, tartaric acid, benzene sulfonic acid, p-toluene sulfonic acid and 10-caphor sulfonic acid.
Patent publication No. WO 2007/035198 discloses crystalline anhydrate form of dodecyl sulfate salt of sitagliptin and process for the preparation thereof.
Patent publication No. WO 2009/085990 discloses crystalline forms of salts of sitagliptin such as sulfuric acid, hydrobromic acid, methane sulfonic acid, acetic acid, benzoic acid, oxalic acid, succinic acid, mandelic acid, fumaric acid, di-p-tolyl-L-tartaric acid and lactic acid and process for the preparation thereof.
Patent publication No. WO 2010/000469 discloses crystalline forms of sitagliptin monobasic, dibasic and tribasic acid addition salts such as hydrochloric acid (Form I and Form II), sulfuric acid (Form I and Form II), methane sulfonic acid (Form I and Form II), fumaric acid (Form I and Form II), malonic acid, malic acid, succinic acid (Form I, Form II and Form III), lactic acid, glycolic acid, maleic acid (Form I and Form II), citric acid (crystalline and amorphous Form), aspartic acid and mandelic acid and process for the preparation thereof.
Patent publication No. WO 2010/012781 (“the '781 publication”) discloses salts of sitagliptin such as ethanedisulfonic acid, galactaric acid, thiocyanic acid, and glutaric acid. The '781 publication further discloses crystalline forms of sitagliptin acid addition salts such as galactaric acid (Form I), L-malic acid (Form I) D-gluconic acid (Form I), succinic acid (Form I), hydrobromic acid (Form I), thiocyanic acid (Form I), oxalic acid (Form I), L-aspartic acid (Form I), ethanedisulfonic acid (Form I), pyroglutamic acid (Form I), glutaric acid (Form I), and acetic acid (Form I).
Patent publication No. WO 2010/092090 discloses acid addition salts of sitagliptin, wherein the acid addition salt is selected from the group consisting of D-glucuronic acid, L-glucuronic acid, glutaric acid, sulfuric acid, L-Lactic acid, D-Lactic acid, ethane sulfonic acid, oxalic acid, acetic acid, L-mandelic acid, D-mandelic acid, capric acid, benzoic acid, hippuric acid, trans-cinnamic acid, malonic acid, citric acid, 1-hydroxy-2-naphtolic acid, crotonic acid and ascorbic acid and process for the preparation thereof.
Patent publication No. WO 2010/117738 discloses crystalline forms of sitagliptin acid addition salts such as sitagliptin sulfate (Form S1, Form S2, Form S3, Form S5, Form S6, Form S7 and Form S8), sitagliptin acetate (Form E1), sitagliptin dibenzoyl-D-tartrate (Form D1 and D2), sitagliptin fumarate (Form F1 and F2), sitagliptin malate (Form M1 and Form M2), sitagliptin oxalate (Form O1 and Form O2), sitagliptin Quinate (Form Q1), sitagliptin succinate (Form U1), sitagliptin mandelate (Form N1, Form N2, Form N3, Form N4 and amorphous form), sitagliptin lactate (Form L1, Form L2, Form L3 and Form L4), sitagliptin maleate (Form A1), sitagliptin S-mandelate (Form N3), sitagliptin L-malate (Form I1), sitagliptin R-(−)-mandelate (Form N5 and Form N6), sitagliptin Orotate (amorphous form).
Patent Publication No. CN101863891 (“the '891 publication”) discloses inorganic salts of sitagliptin such as sodium bisulfate, potassium bisulfate, cesium bisulfate and ammonium bisulfate salt of sitagliptin; sodium dihydrogen phosphate, potassium dihydrogen phosphate, cesium dihydrogen phosphate and ammonium dihydrogen phosphate salt of sitagliptin. The '891 publication further discloses a complex salts of sitagliptin such as sitagliptin sulfate or phosphate salt complex with aminobutanetriol, aminopropanediol, amino ethanol, glucosamine, arginine, ornithine, citrulline or lysine.
Patent publication No. WO 2011/018494 discloses fumarate salt of sitagliptin, wherein the ratio of sitagliptin to fumaric acid is 1:0.6 to 1:1.3 and process for the preparation thereof.
Different salt forms of the same pharmaceutically active moiety differ in their physical properties such as melting point, solubility, etc. These properties may appreciably influence pharmaceutical properties such as dissolution rate and bioavailability. In addition, polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviours (e.g. measured by thermogravimetric analysis (“TGA”), or differential scanning calorimetry (“DSC”), X-ray diffraction pattern (XRPD), infrared absorption fingerprint, and solid state NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
Discovering new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life.
In view of the foregoing, it would be desirable to provide new salt forms of sitagliptin. Further, it would be desirable to have reliable processes for producing these salt forms of sitagliptin. Additionally, the various salt forms of sitagliptin could be used to prepare improved pharmaceutical compositions.